Rebeccamycin derivative containing pharmaceutical composition

ABSTRACT

There are disclosed analogs of the antitumor agent, rebaccamycin, which possess antineoplastic properties against mammalian, particularly experimental animal, tumor systems. The compounds of the invention are aminoalkylated derivatives of rebeccamycin produced by first reacting rebeccamycin with a strong base to obtain a reactive intermediate and then reacting the reactive intermediate with an aminoalkyl compound.

This application is a continuation of application Ser. No. 933,428,filed Nov. 21, 1987, now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to novel compounds having antineoplasticproperties, to their production, to a pharmaceutical compositioncontaining an amount of at least one compound according to the inventionwhich is effective to inhibit the growth of tumors in experimentalanimal systems, and to a method for therapeutically treating anexperimental animal by administering an amount of at least one compoundaccording to the invention which is effective to inhibit tumor growth inan experimental animal system.

2. Background Art

U.S. Pat. Nos. 4,487,925 and 4,552,842 disclose the anti-tumor agentdesignated rebeccamycin, and the 5'-N-methyl and5',2",3",6"-tetraacetate derivatives thereof, and a process forproducing the same agent by cultivating a rebeccamycin-producing strainof Nocardia aerocolonigenes, preferably Nocardia aerocolonigenes ATCC39243, or a rebeccamycin-producing mutant thereof in an aqueous nutrientmedium containing assimilable sources of carbon and nitrogen undersubmerged aerobic conditions until a substantial amount of rebeccamycinis produced.

SUMMARY OF THE INVENTION

This invention comprises analogs of the antitumor agent designatedrebeccamycin (Formula I) ##STR1## produced by first reactingrebeccamycin with a strong base to obtain a reactive intermediate andthen reacting the reactive intermediate with an aminoalkyl halide. Bythe use of an amount of strong base slightly in excess, for exampleabout 10% excess, of the molar equivalent amount of rebeccamycinfollowed by reacting the resulting intermediate with at least one molarequivalent based on rebeccamycin of an aminoalkyl halide as thealkylating agent, there is obtained the corresponding6-aminoalkylrebeccamycin analog. By the use of an amount of strong baseslightly in excess of two-times the molar equivalent amount ofrebeccamycin, for example about 20% excess over two-times the molarequivalent amount of rebeccamycin, and then reacting the resultingintermediate with about one molar equivalent of an aminoalkyl halide asthe alkylating agent, there is obtained the corresponding13-aminoalkylrebeccamycin analog.

DETAILED DESCRIPTION OF THE INVENTION

In one generic aspect, this invention is a compound selected from thegroup consisting of the compounds having the formulas II and III below##STR2## wherein: n is an integer from 1 to 6;

R¹ and R², independently, are selected from hydrogen, unsubstituted andsubstituted C₁ -C₆ alkyl, aralkyl having 1 to 3 carbons in the alkylmoiety and unsubstituted phenyl or phenyl substituted with 1 to 3 alkyl,alkoxy, hydroxy, halo, carboxyl, alkoxycarbonyl, and amino and mono- anddi-lower-alkylamino groups in the aryl moiety, and aryl selected fromunsubstituted phenyl and phenyl substituted with 1 to 3 alkyl, alkoxy,hydroxy, halo, amino, mono- and dialkylamino, nitro, carboxyl,alkoxycarbonyl, and cyano groups provided that both R¹ and R² are noteach aryl and, when taken together, R¹ and R² may be selected from--(CH₂)₄ -- and (CH₂)₂ --R³ --(CH₂)₂ -- to form a 5- or 6-membered ringtogether with the N-atom wherein R³ is selected from CH₂, NH, O and S;

X is selected from H, F, Cl, Br, C₁ -C₃ alkyl, OH, carboxyl,alkoxycarbonyl and alkoxy wherein the alkyl moiety is C₁ -C₃ alkyl,benzyloxy, amino, mon- and dialkylamino; and

R⁴ is selected from H and CH₃ ; and pharmaceutically acceptable acidaddition and base salts thereof.

Preferred, compounds according to this invention having one of FormulasII and III above are those wherein n is an integer from 1 to 6, R¹ andR², independently, are selected from unsubstituted and substituted C₁-C₆ alkyl and, when taken together, R¹ and R² may be selected from--(CH₂)₄ -- and --(CH₂)₂ --R³ --(CH₂)₂ -- to form a 5- or 6-memberedring together with the N-atom wherein R³ is selected from CH₂, NH, O andS, and wherein R₄ is H or CH₃ and X is selected from H, Cl, Br, OH, OCH₃and OCH₂ C₆ H₅.

More preferred compounds according to this invention having one ofFormulas II and III above are those wherein n is selected from theintegers 1, 2 and 3; R¹ and R², independently, are selected from H, C₁-C₃ alkyl, and --(CH₂)₄ --; R⁴ is H or CH₃ ; and X is selected from H,Cl, Br, OH, OCH₃ and OCH₂ C₆ H₅.

Most preferred compounds according to this invention having one ofFormulas II and III above are those wherein n is an integer selectedfrom 2 and 3; X is Cl in each of the 1- and 11-positions of the ringsystem; R¹ and R² are each C₂ H₅ ; and R⁴ is H or CH₃.

The following Table 1 presents representative combinations of the manygroups within the definition of X, n, R¹, R², R³ amd R⁴ and many furthercombinations of such groups will be readily apparent to those skilled inthe art. It is to be understood that the aminoalkyl group, A, bearingthe groups n, R¹ and R² may be substituted at either or both the 6- and13-positions (designated A⁶ and A¹³) of the rebeccamycin ring system. Ofcourse, when only one of A⁶ or A¹³ is aminoalkyl, the other is H.

                  TABLE 1                                                         ______________________________________                                        Representative Substituent Groups                                              ##STR3##                                                                     X            n     R.sup.1     R.sup.2 R.sup.4                                ______________________________________                                        1,11-dichloro                                                                              2     ethyl       ethyl   methyl                                 1,11-dichloro                                                                              3     ethyl       ethyl   methyl                                 3,9-diamino  3     methyl      methyl  H                                      2,10-diamino 4     propyl      propyl  H                                      3,9-dibenzyloxy                                                                            5     i-propyl    H       methyl                                 4,8-dichloro 6     ethyl       H       methyl                                 3,9-dichloro 2     phenethyl   H       methyl                                 4,8-dihydroxy                                                                              3     benzyl      H       methyl                                 3,9-dihydroxy                                                                              2     (CH.sub.2).sub.4  H                                        4,8-dimethoxy                                                                              3     (CH.sub.2).sub.2O (CH.sub.2).sub.2                                                              methyl                                   3,9-dimethoxy                                                                              2     (CH.sub.2).sub.2NH(CH.sub.2).sub.2                                                              methyl                                   4,8-dimethyl 3     (CH.sub.2).sub.5  H                                        3,9-dimethyl 1     (CH.sub.2).sub.2S(CH.sub.2).sub.2                                                               methyl                                   2,10-dimethyl                                                                              2     hexyl       H       methyl                                 3,9-dihydroxycarbonyl                                                                      3     ethyl       ethyl   methyl                                 2,10-dibromo 2     (CH.sub.2).sub.4  methyl                                   H            3     ethyl       ethyl   H                                      ______________________________________                                    

In other aspects, this invention is a pharmaceutical compositioncontaining at least one of the compounds according to the invention anda method for therapeutically treating a mammalian host, for example, anexperimental animal, affected by a malignant tumor by administering atleast one of the compounds according to this invention in a tumorgrowth-inhibiting amount and, usually, by means of administering thecompound in the form of the pharmaceutical composition.

By the expression "C₁ -C₆ alkyl", more particularly unsubstituted C₁ -C₆alkyl, is meant straight-chain or branched-chain or cyclic alkyl groupshaving a total of six carbon atoms. Examples of suitable straight-chainalkyl groups include methyl, ethyl, propyl, butyl, pentyl and hexylgroups. Examples of suitable branched-chain alkyl groups includeisopropyl, sec-butyl, t-butyl, 2-methylbutyl, 2-pentyl, 3-pentyl and thelike groups. Examples of suitable cyclic alkyl groups includecyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups. The alkylgroups may be substituted, generally with 1 or 2 substituents, withsubstituents selected from halo, hydroxy, alkoxy, amino, mono- anddialkylamino, nitro, carboxyl, alkoxycarbonyl, and cyano groups. By theexpression "aralkyl" is meant benzyl, phenethyl (phenylethyl) andphenylpropyl groups wherein the phenyl moiety may be substituted. By theexpression "aryl" is meant phenyl. The aralkyl or aryl group may containsubstituted phenyl wherein the substituent may be from 1 to 3 alkyl,hydroxy, alkoxy, halo, amino, mono- and dialkylamino, nitro, carboxyl,alkoxycarbonyl, and cyano groups.

As used herein, the expression "halo" is meant in the conventional senseto include F, Cl, Br, and I.

When the expressions alkoxy, alkoxycarbonyl, mono- and dialkylamino areused, these expressions usually are meant to include an alkyl moietyhaving 1 to 3 carbon atoms.

As mentioned above, R¹ and R² are not each aryl. Also, R¹ and R²generally are not each selected from the sterically larger of the C₁ -C₆alkyl and from aralkyl groups. Preferably, when R¹ and R² are eachalkyl, they are each selected from C₁ -C₃ alkyl groups.

As is mentioned above, rebeccamycin is a known antitumor agent disclosedin U.S. Pat. Nos. 4,487,525 and 4,552,842. The Chemical Abstractsnomenclature for rebeccamycin is as follows: 5H-Indolo[2,3-a] pyrrolo[3,4-c] carbazole-5,7 (6H)dione, 1, 11-dichloro-12,13-dihydro-12-(4-O-methyl-beta-D-glucopyranosyl). However, the name"rebeccamycin" is used throughout for simplicity although the ChemicalAbstracts numbering systems is used to identify the various positions inthe rebeccamycin ring system.

The starting material for the most preferred compounds according to thisinvention is rebeccamycin itself. Rebeccamycin, Formula I, may beproduced by cultivating a rebeccamycin-producing strain of Nocardiaaerocolonigenes, preferably a strain having the characteristics ofNocardia aerocolonigenes strain C38,383-RK2(ATCC39243) or a mutantthereof under submerged aerobic conditions in an aqueous nutrient mediumas is described in U.S. Pat. Nos. 4,487,925 and 4,552,842.

Derivatives of rebeccamycin havin various groups substituted on therebeccamycin ring system in place of the 1,11-dichloro substituents maybe used as starting materials in the place of rebeccamycin to obtaincompounds within the broad definition and preferred and more preferredembodiments according to the present invention. For example,didechlororebeccamycin can be produced by subjecting rebeccamycin tohydrogenolysis and the resulting intermediate may be subjected toalkylation using strong base followed by reaction of the intermediatefrom the strong base treatment with a suitable aminoalkyl halide. Otherchromophores of rebeccamycin having various substituents on therebeccamycin ring system can be produced using methods disclosed by T.Kaneko et al., Tetrahedron Letters, 26, 4015 (1985). For example, byusing the procedures therein disclosed, compounds having the followingformula, IV, were produced: ##STR4##

The following more particularly describes a typical synthesis ofcompounds with chromophores similar or identical to that of rebeccamycinhaving various substituents on the ring system in the place of the Clgroups. Treatment of a substituted indole with methyl magnesiumtetrahydrofuran produces a solution of indole Grignard (VI). Twoequivalents of this solution and one equivalent of N-benzyloxymethyl3,4-dibromo-maleimide gives an adduct of formula VII. This can be eitherphotochemically cyclized by irradiation at 300 nm in a benzene solutioncontaining a small amount of I₂ or thermally by refluxing a solution ofthe adduct in benzene in the presence of Ag₂ O. The intermediate thusprepared (VIII) is then coupled with O-acylated 1-halosugar in thepresence of Ag₂ O to give N-glycoside IX. A catalytic hydrogenation toremove the N6 protecting group and a base hydrolysis of the sugar O-acylgroups gives the desired product X. Illustrative of the substitutedindoles that can be used in this preparation are listed in Table 2.##STR5##

Table 2--Starting Indoles

5-Aminoindole

6-Aminoindole

5-Benzyloxyindole

4-Chloroindole

5-Chloroindole

4-Hydroxyindole

5-Hydroxyindole

Indole

4-Methoxyindole

5-Methoxyindole

4-Methylindole

5-Methylindole

6-Methylindole

Indole-5-carboxylic acid

Glycosidation of any one of the three chromophores represented byFormula IV or a chromophore represented by Formula X by reaction with anappropriate glycosyl halide provides a rebeccamycin derivative. And,reaction of the rebeccamycin derivative first with strong base followedby an aminoalkyl halide provides analogs of rebeccamycin according tothis invention having one of Formulas II or III.

Having obtained rebeccamycin or a related compound with the samechromosphore this starting material is first dissolved in a suitableinert solvent, for example dimethylformamide (DMF), dimethylsulfoxide(DMSO), tetrahydrofuran (THF) or other anhydrous, aprotic solvent andthen reacted with a strong base in an inert atmosphere, for example inan argon or nitrogen atmosphere. Although any strong base that iscompatible with the starting material and solvent may be used, forexample, KNH₂ or KH or NaNH₂ or NaH or lithium diisopropyl amide (LDA)or lithium hexamethyl disalazide or KOtBu or Grignard reagent such asMeMgBr or NaNH₂ or NaH or equivalent base, NaH may be advantageouslyemployed.

It has been discovered that by using strong base, for example NaH, in anamount slightly in excess of the molar equivalent of the amount ofstarting material, for example in the range of from about 5% to about15% and preferably about 10% (9-11%) excess, followed by treatment withat least one molar equivalent based on rebeccamycin starting material ofan appropriate aminoalkyl compound, there may be obtained a compoundaccording to the invention having an aminoalkyl substituent on theN-atom in the 6-position of the rebeccamycin ring system.

Further, it has been discovered that by using strong base, for exampleNaH, in a relatively large excess amount such as an amount slightly inexcess of two-times the molar equivalent of the amount startingmaterial, for example, in the range of about 15% to about 25% andpreferably about 20% (18-22%) excess, followed by treatment with anappropriate aminoalkyl compound in an amount about the molar equivalentof starting material, there may be obtained a compound according to theinvention having an aminoalkyl substituent on the N-atom in the13-position of the rebeccamycin ring system.

When more than two equivalents of base are used, a dianion at N6 and N13is formed. Since the N13 anion is more reactive than the N6 anion, a N13aminoalkyl derivative is obtained when only one equivalent of aminoalkylhalide is used. When two equivalents of aminoalkyl halide is used, theN6,N13-diaminoalkyl derivative may be obtained.

Following the reaction of the starting material with a in situ with anappropriate reactive aminoalkyl compound by adding the aminoalkylcompound to the mixture of starting material and strong base andintermediate reaction product threof in inert solvent. Any aminoalkylcompound that is compatible with the starting material and product andsolvent may be used, for example an aminoalkyl halide or sulfonate andthe like, represented by the formula L-(CH₂)_(n) --NR¹ R² wherein n, R¹amd R² are as defined above and L is a leaving group such as halide ormethanesulfonate or p-toluenesulfonate. Generally an aminoalkyl halidesuch as, for example, diethylaminoethyl chloride and diethylaminopropylchloride, may be advantageously employd.

Generally, the reaction of strong base with starting material may becarried-out advantageously at about room temperature, that is, at about18° C. to about 22° C. The mixture of starting material and strong base,generally, may be stirred for a period of a few minutes to severalhours; however, the reaction is usually complete in about 20-30 minutes.

Then, there is added to the stirred mixture of starting material andstrong base and resulting reactive intermediate reaction product thereofin inert solvent the appropriate aminoalkyl compound and the resultingmixture may be stirred at room temperature for about 20-24 hours or atabout 4° C. for a shorter period of time, for example, six hours untilthe reaction of the reactive intermediate with aminoalkyl compound iscomplete.

The compounds of Formulas II and III according to this invention may beprovided as pharmaceutically acceptable acid addition and base saltsprovided that the anion or cation thereof did not contributesignificantly to the toxicity of the salt and that the salts arecompatible with the standard and conventional pharmaceutical carriersand other conventional adjuvants and excipients customarily employed inproducing pharmaceutical compositions adapted for oral or parenteraladministration. The acid addition salts are formed by conventionaltechniques involving reaction of compounds of Formulas II and III with amineral acid or organic carboxylic and sulfonic acids. Examples ofsuitable mineral acids include hydrochloric acid, phosphoric acid, andthe like. Examples of suitable organic acids include acetic acid, citricacid, maleic acid, succinic acid, benzoic acid, tartaric acid, ascorbicacid, methanesulfonic acid, p-toluenesulfonic acid, and the like.

The base salts are formed by conventional techniques involving reactionof the compounds of Formulas II and III with alkali (Na, K) andalkalkine earth (Ca, Zn, Ba, Mg, and Mn) metal bases, more preferablywith alkali metal bases, and by reaction with amines. Suitable basesinclude the hydroxide, carbonate or bicarbonate salts of the metalsmentioned above such as, for example, sodium and potassium hydroxides,sodium and potassium carbonates, and sodium and potassium bicarbonatesand the corresponding calcium and zinc salts. Additional suitable basesinclude ammonium salts those formed by reaction of compounds of formulasII and III with triethylamine, dibenzylamine, N,N'-dibenzylethylenediamine, procaine, and equivalent amines.

The pharmaceutical carrier may be solid or liquid to provide solid orliquid compositions. Solid form compositions suitable for oraladministration include powders, tablets, capsules, caplets, dispersiblegranules, and cachets. Suitable solid carriers include at least onecarrier substance which may function only as a carrier or may inaddition serve a further function such as a diluent, flavoring agent,solubilizer, lubricant, suspending agent, binder, tablet disintegratingagent, encapsulating agent and te like. Inert solid carriers include, toname but a few, magnesium carbonate and stearate, talc, sugar, lactose,pectin, dextrin, starch, gelatin, cellulosic materials, and the like.The compounds according to the invention may be provided as sterilesoluble compounds or compositions, including solutions and suspensionsand emulsions, thereof which can be dissolved in sterile water or otherliquid medium for oral administration or for parenteral administration.Examples of liquid carriers suitable for oral administration includewater, alcohol, polypropylene glycol, polyethylene glycol and mixturesof two or more of the above. Examples of liquid carriers suitable forparenteral use include water-for-injection, physiological aline, andother suitable sterile injection media. Suitable buffers for use withthe liquid carrier to provide, generally, a suitable buffered isotonicsolution include trisodium orthophosphate, sodium bicarbonate, sodiumcitrate, N-methylglucamine, L(+)-lysine, and L(+)-arginine to name but afew representative buffering agents.

The pharmaceutical composition will contain an amount of activecomponent, that is, compound of Formula II or III or mixture thereof,which may be varied or adjusted widely depending upon the particularapplication, the form, the potency of the particular compound used, andthe desired concentration of compound in the composition. Generally, theamount of active component will range between about 0.5-90% by weightbased on total weight of composition.

In therapeutic use for treating a mammalian host, for example anexperimental animal host, affected by a malignant tumor, the compoundsof this invention will be administered in an amount effective to inhibitthe growth of the tumor, that is, a tumor growth-inhibiting amount ofdosage. Generally, the tumor growth-inhibiting amount will be in therange of about 0.1 to about 15 mg/kg of animal body weight/day. It is tobe understood that the actual preferred dosage of compound will varywidely depending upon the requirements of the animal being treated, theparticular animal host and situs and disease being treated, thecomposition being used, and the route of administration. Many factorsthat modify the action of the anti-neoplastic agent will be taken intoaccount by one skilled in the art to which this invention pertainsincluding, for example, age, body weight and sex of the animal host;diet; time of administration; rate of excretion; condition of the host;severity of the disease; and the like. Administration may be carried outsimultaneously or periodically within the maximum tolerated dose.Optimal administration (or application) rates for a given set ofconditions may be readily ascertained by those skilled in the art usingconventional dosage determination tests.

The following examples are presented to illustrate but a fewrepresentative embodiments of this invention and are not to be construedas limiting in scope. All parts and percentages are by weight and alltemperatures are in degrees Celsius unless otherwise indicated.

Rebeccamycin analogs according to this invention were tested forantitumor activity against the transplanted mouse leukemia P-388according to the procedures of Geran et al. reported in CancerChemother. Rpts., 3, 1-103 (1972). Prolongation of survival of leukemicmice was observed at several dosage levels ranging from 6 mg/kg bodywt/day to 100 mg/kg body wt./day. Results of the tests are shown in theaccompanying Table 3. The standard, comparison agent is selected fromolivomycin and mitomycin C. These results illustrate that therebeccamycin analogs according to the invention possess usefulantineoplastic activity.

EXAMPLE 1. 6-(2-Diethylaminoethyl)rebeccamycin

DMF (100 mL) was added under argon to a mixture of rebeccamycin (990 mg,1.74 mmol) and NaH (46 mg, 1.91 mmol). After 20 minutes of stirring atroom temperature, 2-diethylaminoethyl chloride (524 mg, 3.86 mmol) wasadded.

The resulting mixture was stirred for 24 h. and the reaction was thenquenched by addition of 1% aq HCl solution. The reaction mixture wasbasified by addition of saturated NaHCO₃ solution and extracted withEtOAc.

The organic layer was collected and washed with brine and dried over Na₂SO₄. The residue obtained by evaporation of the solvent waschromatographed on silica gel (elution with EtOAc) to give 770 mg (66%)of the title compound: mp>250° C.; NMR (DMSO-d₆) δ 10.68 (s, 1H), 9.26(d, 1H, J=7.8 Hz), 9.08 (d, 1H, J=7.9 Hz), 7.73 (d, 1H, J=8.9 Hz), 7.70(d, 1H, J=8.9 Hz), 7.45 (t, 2H, J=7.8 Hz), 6.94 (d, 1H, J=9.1 Hz), 5.43(d, 1H, J=5.6 Hz), 5.31 (bs, 1H), 5.03 (d, 1H J=5.7 Hz), 395 (s, 2H),3.82 (m, 2H), 3.70-3.48 (m, 7H), 2.72 (m, 2H), 2.53 (m, 4H), 0.94 (t,6H, J=7.0 Hz); IR (KBr) 3343, 1692, 1381, 1070, 760 cm⁻¹ ; FABMS 669(M+1), 493, 217 m/e.

EXAMPLE 2. 6-(2-Diethylaminoethyl)rebeccamycin hydrochloride

To a solution of 6-(2-diethylaminoethyl)rebeccamycin (770 mg, 1.15 mmol)in 30 mL of THF at 0° C. was added one equivalent of 5.6M ethanolic HClsolution. After stirring 3 h at 0° C. the resulting precipate wascollected by filtration and washed with diethyl ether to give 728 mg(90%) of the title compound: mp >250° C.; NMR (DMSO-d₆) δ10.7 (s, 1H),10.16 (s, 1H), 9.23 (d, 1H, J=8.1 Hz), 9.05 (d, 1H, J=8.0 Hz), 7.74 (d.1H, J=8.5), 7.72 (d, 1H, J=9.3 Hz), 7.46 (t, 2H, J=8.1 Hz), 6.94 (d, 1H,H=9.1 Hz), 5.47 (bs, 1H), 5.36 (bs, 1H), 5.08 (bd, 1H, J=3.8 Hz), 4.11(t, 2H, J=6.3 Hz), 3.97 (bs, 1H), 3.85 (d, 1H, J=9.5 Hz), 3.66-3.57 (m,7H), 3.49-3.20 (m, 7H), 1.26 (t, 6H, J=7.0 Hz); IR (KBr) 3336, 1699,1416, 1381, 1084, 760 cm⁻¹ ; FABMS 669 (M+1), 635, 493 m/e.

EXAMPLE 3. 6-(3-Diethylaminopropyl)rebeccamycin

DMF (20mL) was added under argon to a mixture of rebeccamycin (162 mg,0.28 mmol) and NaH (7.5 mg, 0.31 mmol). To this solution was added 110mg (0.78 mmol) of 3-diethylaminopropyl chloride. The resulting solutionwas stirred and warmed to 40° C. for 6 h. A workup similar to Example 1gave 55 mg (28%) of the title compound: NMR (DMSO-d₆) δ 5 9.28 (d, 1H,J=7.8 Hz), 9.10 (d, 1H, J=8.1 Hz), 7.73 (d, 1H, J=9.4 Hz), 7.70 (d, 1H,J=9.4 Hz), 7.45 (d, 1H, J=7.8 Hz), 6.94 (d, 1H, J=9.1 Hz), 5.42 (bd, 1H,J=5.8 Hz), 5.31 (bs, 1H), 5.03 (bs, 1H), 3.95 (bs, 2H), 3.82-3.59 (m,9H), 2.44 (m, 6H), 1.81 (m, 2H), 0.90 (t, 6H, J=7.0 Hz); IR (KBr), 3328,1691, 1376, 1052, 755 cm⁻¹ ; MS 682 (M), 653, 403, 393 m/e.

EXAMPLE 4. 6-(3-Diethylaminopropyl)rebeccamycin hydrochloride

Treatment of the product from Example 3 with ethanolic HCl in a similarmanner as Example 2 gave the title compound in 89% yield: mp>250° C.;NMR (DMSO-d₆) δ 5 10.70 (s, 1H), 9.81 (bs, 1H), 9.26 (d, 1H, J=7.1 Hz),9.09 (d, 1H, J=8.0 Hz), 7.73 (d, 1H, J=11.4 Hz), 7.72 (d, 1H, J=11.0Hz), 7.43 (t, 2H, J=7.9 Hz), 6.94 (d, 1H, J=9.2 Hz), 5.46 (bs, 1H), 5.34(bs, 1H), 5.06 (bs, 1H), 3.95 (bs, 2H), 3.83 (m, 2H), 3.66-3.54 (m, 5H),3.20 (m, 2H), 3.10 (m, 4H), 2.12 (m, 2H), 1.18 (t, 6H, J=7.2 Hz); IR(KBr) 3343, 1692, 1452, 1070, 760 cm⁻¹ ; FABMS 683, (M+1), 507, 406 m/e.

EXAMPLE 5. 13-(3-Dethylaminopropyl)rebeccamycin

DMF (25 mL) was added under argon to a mixture of rebeccamycin (188 mg,0.33 mmol) and NaH (17 mg 0.73 mmol). After a few minutes of stirring atroom temperature, 3-diethylmainopropyl chloride (54 mg, 0.36 mmol) wasadded and the resulting solution was stirred at room temperature for 22h. The reaction was quenched by addition of 10% HCl solution in water.Saturated NaHCO₃ solution was added to basify the solution and theproduct was extracted with EtOAc. The organic layer was collected andwashed with brine and dried over MgSO₄. The residue obtained afterevaporation of the solvent was chromatographed on neutral alumnina (10%MeOH-acetone) to give 76 mg (34%) of the title compound: mp 203°-204°C.; NMR (DMSO-d₆) δ 10.67 (s, 1H), 9.28 (d, 1H, J=8.1 Hz), 9.10 (d, 1H,J=8.1 Hz), 7.73 (d, 1H, J= 10.9 Hz), 7.71 (d, 1H, J=11,6 Hz), 7.45 (t,2H, J=8.1 Hz), 6.94 (d, 1H, J=9.0 Hz), 5.43 (d, 1H, J=5.8 Hz), 5.32 (t,1H, J=5.2 Hz), 5.03 (D, 1H, J=5.5 Hz), 3.96 (m, 2H), 3.85-3.79 (m, 3H),3.91-3.53 (m, 5H), 2.71 (m, 4H) 1.95 (m, 2H), 1.13 (m, 6H); IR (KBr)3343, 1696, 1388, 1085, 760 cm⁻¹ ; MS 683 (M+1), 654, 506 m/e.

                  TABLE 3                                                         ______________________________________                                        EFFECT OF REBECCAMYCIN ANALOGS ON P-388                                       LEUKEUMIA                                                                                         Median                                                                        Survival         Avg. wt.                                           Dose, IP  Time (MST)  %    change,                                  Compound  mg/kg/inj Days        T/C  gm day 4                                 ______________________________________                                        Olivomycin                                                                              0.8       17.0        162  -2.4                                               0.4       13.5        129  -2.6                                     Ex. 1     100       13.0        124  -2.0                                               50        17.5        167  -2.2                                               25        14.0        133  -0.5                                     Mitomycin C                                                                             4.8       19.0        211  -2.0                                               3.2       22.0        244  -1.5                                     Ex. 2     8.0       12.0        133  -0.4                                               6.0       12.5        139  -0.0                                     Ex. 4     8.0       12.5        139  -0.9                                               6.0       13.0        144   0.1                                     ______________________________________                                    

What is claimed is:
 1. A pharmaceutical composition comprising a tumorgrowth-inhibiting amount of about 0.5-90% by weight based on totalweight of composition of at least one compound selected from the groupof compounds having the formulas ##STR6## wherein n is an integer from 1to 6;R¹ and R², independently, are selected from hydrogen, unsubstitutedand substituted C₁ -C₆ alkyl, aralkyl having 1 to 3 carbons in the alkylmoeity and unsubstituted phenyl or phenyl substituted with 1 to 3 alkyl,alkoxy, hydroxy, halo, carboxyl, alkoxycarbonyl and amino and mon- anddi-lower-alkylamino groups in the aryl moiety, and aryl selected fromunsubstituted phenyl and phenyl substituted with 1 to 3 alkyl, alkoxy,hydroxy, halo, amino, mono- and dialkylamino, nitro, carboxyl,alkoxycarbonyl and cyano groups provided that both R¹ and R² are noteach aryl and, when taken together, R¹ and R² may be selected from--(CH₂)₄ -- and (CH₂)₂ --R³ --(CH₂)₂ -- to form a 5- or 6-membered ringtogether with the N-atom wherein R³ is selected from CH₂, NH, O and S; Xis selected from H, F, Cl, Br, C₁ -C₃ alkyl, OH, carboxyl,alkoxycarbonyl and alkoxy wherein the alkyl moiety is C₁ -C₃ alkyl, andbenzyloxy; and R⁴ is selected from H and CH₃ ; and pharmaceuticallyacceptable acid addition and base salts thereof, and a pharmaceuticallyacceptable carrier.